Dosing regimens of celgosivir for the treatment of dengue

Abstract

Methods of treating a dengue virus (DENV) infection in a human subject, comprising administering to the human subject a compound of Formula (I), or pharmaceutical composition comprising a compound of Formula (I): A compound of Formula (I) can be administered within onset of fever to 72 hours of fever onset due to dengue infection and then every 6 to 12 hours until there is an improvement in the infection or between from about 1 day to about 10 days. The methods of the invention can be used to treat primary and secondary DENV1-4 viral infections.

What is claimed is: 
     
       1. A method of treating a dengue virus (DENV) infection in a human subject, comprising:
 a) administering to the human subject an initial dose of about 100 to about 600 mg of a compound of Formula (II), or a pharmaceutical composition comprising a compound of Formula (II), within from about onset of fever to about 72 hours of fever onset due to dengue infection; and 
 b) administering to the human subject a dose of about 25 to about 300 mg of a compound of Formula (II), or a pharmaceutical composition comprising a compound of Formula (II), at intervals of from about 6 to about 12 hours until there is an improvement in the infection or between from about 1 day to about 10 days, Formula (II), having the following structure, 
 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
       2. A method of treating a secondary dengue infection in a human subject, comprising:
 a) administering to the human subject an initial dose of about 100 to about 600 mg of a compound of Formula (II), or a pharmaceutical composition comprising a compound of Formula (II), within from about onset of fever to about 72 hours of fever onset due to dengue infection; and 
 b) administering to the human subject a dose of about 25 to about 300 mg of a compound of Formula (II), or a pharmaceutical composition comprising a compound of Formula (II), at intervals of from about 6 to about 12 hours until there is an improvement in the infection or between from about 1 day to about 10 days, Formula (II) having the following structure, 
 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
       3. A method of treating a dengue virus (DENV) infection in a human subject, comprising:
 a) administering orally to the human subject an initial dose of about 100 to about 600 mg of a compound of Formula (II), or a pharmaceutical composition comprising a compound of Formula (II), within from about onset of fever to about 72 hours of fever onset due to dengue infection; and 
 b) administering orally to the human subject a dose of about 25 to about 300 mg of a compound of Formula (II), or a pharmaceutical composition comprising a compound of Formula (II), at intervals of from about 6 to about 12 hours until there is an improvement in the infection or between from about 1 day to about 10 days, Formula (II) having the following structure, 
 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
       4. The method of  claim 1  or  claim 2 , wherein the human subject is an adult or a child. 
     
     
       5. The method of  claim 1 , wherein the compound of Formula (II) is converted to castanospermine after administration to a human subject. 
     
     
       6. The method of  claim 1 , wherein a steady state Cmin serum or plasma concentration of between about 0.05 and about 2.0 microgram/mL of castanospermine in an adult or child human subject is attained after treatment. 
     
     
       7. The method of  claim 1 , wherein a steady state Cmin serum or plasma concentration of between about 1.0 and about 2.0 microgram/mL of castanospermine in an adult or child human subject is attained after treatment. 
     
     
       8. The method of  claim 1 , wherein a steady state Cmin serum or plasma concentration of between about 1.0 and about 1.5 microgram/mL of castanospermine in an adult or child human subject is attained after treatment. 
     
     
       9. The method of  claim 1 , wherein a steady state Cmin serum or plasma concentration of between about 1.5 and about 2.0 microgram/mL of castanospermine in an adult or child human subject is attained after treatment. 
     
     
       10. The method of  claim 1 , wherein a steady state Cmin serum or plasma concentration of between about 1.25 and about 1.75 microgram/mL of castanospermine in an adult or child human subject is attained after treatment. 
     
     
       11. The method of  claim 1 , wherein dengue viral infection comprises at least one dengue virus selected from DENV1, DENV2, DENV3 and DENV4. 
     
     
       12. The method of  claim 1 , wherein the dengue viral infection is secondary dengue infection. 
     
     
       13. The method of  claim 1 , wherein the human subject to be treated is positive prior to treatment for a dengue infection using a NS1 strip assay or quantitative PCR. 
     
     
       14. The method of  claim 1 , wherein the virological log reduction in treated human subjects is at least 50% greater than untreated or placebo-treated groups. 
     
     
       15. The method of  claim 1 , wherein administering the compound, or the pharmaceutical composition, achieves a steady state Cmin serum or plasma concentration of between about 0.05 and about 2.0 microgram/mL of castanospermine. 
     
     
       16. The method of  claim 1 , wherein administering the compound, or the pharmaceutical composition, achieves a steady state Cmin serum or plasma concentration of between about 1.0 and about 2.0 microgram/mL of castanospermine. 
     
     
       17. The method of  claim 1 , wherein administering the compound, or the pharmaceutical composition, achieves a steady state Cm in serum or plasma concentration of between about 1.0 and about 1.5 microgram/mL of castanospermine. 
     
     
       18. The method of  claim 1 , wherein administering the compound, or the pharmaceutical composition, achieves a steady state Cmin serum or plasma concentration of between about 1.5 and about 2.0 microgram/mL of castanospermine. 
     
     
       19. The method of  claim 1 , wherein administering the compound, or the pharmaceutical composition, achieves a steady state Cmin serum or plasma concentration of between about 1.25 and about 1.75 microgram/mL of castanospermine. 
     
     
       20. The method of  claim 1 , wherein the compound, or the pharmaceutical composition, is administered intravenously, orally, rectally, or sublingually. 
     
     
       21. The method of  claim 1 , wherein the human subject is administered an initial dose of 150 mg and a dose of 100 mg is thereafter administered to the human subject every 6 hours, 8 hours, or 12 hours for about 1 day, about 2 days, or about 5 days. 
     
     
       22. The method of  claim 1 , wherein the human subject is administered an initial dose of 150 mg and a dose of 150 mg is thereafter administered to the human subject every 6 hours for about 1 day, about 2 days, or about 5 days. 
     
     
       23. The method of  claim 1 , wherein the human subject is administered an initial dose of 150 mg and a dose of 150 mg is thereafter administered to the human subject every 8 hours for about 1 day, about 2 days, or about 5 days. 
     
     
       24. The method of  claim 1 , wherein the human subject is administered an initial dose of 150 mg and a dose of 150 mg is thereafter administered to the human subject every 12 hours for about 1 day, about 2 days, or about 5 days. 
     
     
       25. The method of  claim 1 , wherein the human subject is administered an initial dose of 150 mg and a dose of 200 mg is thereafter administered to the human subject every 6 hours, 8 hours, or 12 hours for about 1 day, about 2 days, or about 5 days. 
     
     
       26. The method of  claim 1 , wherein the human subject is administered an initial dose of 200 mg and a dose of 100 mg is thereafter administered to the human subject every 6 hours, 8 hours, or 12 hours for about 1 day, about 2 days, or about 5 days. 
     
     
       27. The method of  claim 1 , wherein the human subject is administered an initial dose of 200 mg and a dose of 150 mg is thereafter administered to the human subject every 6 hours, 8 hours, or 12 hours for about 1 day, about 2 days, or about 5 days. 
     
     
       28. The method of  claim 1 , wherein the human subject is administered an initial dose of 200 mg and a dose of 200 mg is thereafter administered to the human subject every 6 hours, 8 hours, or 12 hours for about 1 day, about 2 days, or about 5 days. 
     
     
       29. The method of  claim 1 , wherein the human subject is administered a single or a divided dose of about 25 to about 300 mg of the compound or the pharmaceutical composition, for about between about 5 days to about 10 days. 
     
     
       30. The method of  claim 29 , wherein the human subject is administered a divided dose of about 25 to about 300 mg of the compound, or the pharmaceutical composition, for about between about 5 days to about 10 days. 
     
     
       31. A method of treating a dengue virus (DENV) infection in a plurality of human subjects, comprising:
 a) administering to each of the plurality of human subjects an initial dose of about 100 to about 600 mg of a compound of Formula (II), or a pharmaceutical composition comprising a compound of Formula (II), within from about onset of fever to about 72 hours of fever onset due to dengue infection; and 
 b) administering to each of the plurality of human subjects a dose of about 25 to about 300 mg of a compound of Formula (II), or a pharmaceutical composition comprising a compound of Formula (II), at intervals of from about 6 to about 12 hours until there is an improvement in the infection or between from about 1 day to about 10 days, Formula (II) having the following structure, 
 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
       32. A method of treating a secondary dengue infection in a plurality of human subjects, comprising:
 a) administering to each of the plurality of human subjects an initial dose of about 100 to about 600 mg of a compound of Formula (II), or a pharmaceutical composition comprising a compound of Formula (II), within from about onset of fever to about 72 hours of fever onset due to dengue infection; and 
 b) administering to each of the plurality of human subjects a dose of about 25 to about 300 mg of a compound of Formula (II), or a pharmaceutical composition comprising a compound of Formula (II), at intervals of from about 6 to about 12 hours until there is an improvement in the infection or between from about 1 day to about 10 days, Formula (II) having the following structure, 
 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
       33. A method of treating a dengue virus (DENV) infection in a plurality of human subjects, comprising:
 a) administering orally to each of the plurality of human subjects an initial dose of about 100 to about 600 mg of a compound of Formula (II), or a pharmaceutical composition comprising a compound of Formula (II), within from about onset of fever to about 72 hours of fever onset due to dengue infection; and 
 b) administering orally to each of the plurality of human subjects a dose of about 25 to about 300 mg of a compound of Formula (II), or a pharmaceutical composition comprising a compound of Formula (II), at intervals of from about 6 to about 12 hours until there is an improvement in the infection or between from about 1 day to about 10 days, Formula (II) having the following structure, 
 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
       34. The method of  claim 31  or  claim 32 , wherein the plurality of human subjects includes adults and/or children. 
     
     
       35. The method of  claim 31 , wherein the compound of Formula (II) is converted to castanospermine after administration to each of the plurality of human subjects. 
     
     
       36. The method of  claim 31 , wherein an average steady state Cmin serum or plasma concentration of between about 0.05 and about 2.0 microgram/mL of castanospermine in the plurality of human subjects is attained after treatment. 
     
     
       37. The method of  claim 31 , wherein an average steady state Cmin serum or plasma concentration of between about 1.0 and about 2.0 microgram/mL of castanospermine in the plurality of human subjects is attained after treatment. 
     
     
       38. The method of  claim 31 , wherein an average steady state Cmin serum or plasma concentration of between about 1.0 and about 1.5 microgram/mL of castanospermine in the plurality of human subjects is attained after treatment. 
     
     
       39. The method of  claim 31 , wherein an average steady state Cmin serum or plasma concentration of between about 1.5 and about 2.0 microgram/mL of castanospermine in the plurality of human subjects is attained after treatment. 
     
     
       40. The method of  claim 31 , wherein an average steady state Cmin serum or plasma concentration of between about 1.25 and about 1.75 microgram/mL of castanospermine in the plurality of human subjects is attained after treatment. 
     
     
       41. The method of  claim 31 , wherein dengue viral infection comprises at least one dengue virus selected from DENV1, DENV2, DENV3 and DENV4. 
     
     
       42. The method of  claim 31 , wherein the dengue viral infection is secondary dengue infection. 
     
     
       43. The method of  claim 31 , wherein each of the plurality of human subjects to be treated is positive prior to treatment for a dengue infection using a NS1 strip assay or quantitative PCR. 
     
     
       44. The method of  claim 31 , wherein the virological log reduction in treated plurality of human subjects is at least 50% greater than untreated or placebo-treated groups. 
     
     
       45. The method of  claim 31 , wherein administering the compound, or the pharmaceutical composition, achieves an average steady state Cmin serum or plasma concentration in the plurality of human subjects of between about 0.05 and about 2.0 microgram/mL of castanospermine. 
     
     
       46. The method of  claim 31 , wherein administering the compound, or the pharmaceutical composition, achieves an average steady state Cmin serum or plasma concentration in the plurality of human subjects of between about 1.0 and about 2.0 microgram/mL of castanospermine. 
     
     
       47. The method of  claim 31 , wherein administering the compound, or the pharmaceutical composition, achieves an average steady state Cmin serum or plasma concentration in the plurality of human subjects of between about 1.0 and about 1.5 microgram/mL of castanospermine. 
     
     
       48. The method of  claim 31 , wherein administering the compound, or the pharmaceutical composition, achieves an average steady state Cmin serum or plasma concentration in the plurality of human subjects of between about 1.5 and about 2.0 microgram/mL of castanospermine. 
     
     
       49. The method of  claim 31 , wherein administering the compound, or the pharmaceutical composition, achieves an average steady state Cmin serum or plasma concentration in the plurality of human subjects of between about 1.25 and about 1.5 microgram/mL of castanospermine. 
     
     
       50. The method of  claim 31 , wherein the compound, or the pharmaceutical composition, is administered intravenously, orally, rectally, or sublingually. 
     
     
       51. The method of  claim 31 , wherein each of the plurality of human subjects is administered an initial dose of 150 mg and a dose of 100 mg is thereafter administered to each of the plurality of human subjects every 6 hours, 8 hours, or 12 hours for about 1 day, about 2 days, or about 5 days. 
     
     
       52. The method of  claim 31 , wherein each of the plurality of human subjects is administered an initial dose of 150 mg and a dose of 150 mg is thereafter administered to each of the plurality of human subjects every 6 hours for about 1 day, about 2 days, or about 5 days. 
     
     
       53. The method of  claim 31 , wherein each of the plurality of human subjects is administered an initial dose of 150 mg and a dose of 150 mg is thereafter administered to each of the plurality of human subjects every 8 hours for about 1 day, about 2 days, or about 5 days. 
     
     
       54. The method of  claim 31 , wherein each of the plurality of human subjects is administered an initial dose of 150 mg and a dose of 150 mg is thereafter administered to each of the plurality of human subjects every 12 hours for about 1 day, about 2 days, or about 5 days. 
     
     
       55. The method of  claim 31 , wherein each of the plurality of human subjects is administered an initial dose of 150 mg and a dose of 200 mg is thereafter administered to each of the plurality of human subjects every 6 hours, 8 hours, or 12 hours for about 1 day, about 2 days, or about 5 days. 
     
     
       56. The method of  claim 31 , wherein each of the plurality of human subjects is administered an initial dose of 200 mg and a dose of 100 mg is thereafter administered to each of the plurality of human subjects every 6 hours, 8 hours, or 12 hours for about 1 day, about 2 days, or about 5 days. 
     
     
       57. The method of  claim 31 , wherein each of the plurality of human subjects is administered an initial dose of 200 mg and a dose of 150 mg is thereafter administered to each of the plurality of human subjects every 6 hours, 8 hours, or 12 hours for about 1 day, about 2 days, or about 5 days. 
     
     
       58. The method of  claim 31 , wherein each of the plurality of human subjects is administered an initial dose of 200 mg and a dose of 200 mg is thereafter administered to each of the plurality of human subjects every 6 hours, 8 hours, or 12 hours for about 1 day, about 2 days, or about 5 days. 
     
     
       59. The method of  claim 31 , wherein each of the plurality of human subjects is administered a single or a divided dose of about 25 to about 300 mg of the compound or the pharmaceutical composition, for about between about 5 days to about 10 days. 
     
     
       60. The method of  claim 59 , wherein each of the plurality of human subjects is administered a divided dose of about 25 to about 300 mg of the compound, or the pharmaceutical composition, for about between about 5 days to about 10 days. 
     
     
       61. The method of  claim 1 , wherein said doses of step b) are administered at least 3 times per day. 
     
     
       62. The method of  claim 2 , wherein said doses of step b) are administered at least 3 times per day. 
     
     
       63. The method of  claim 3 , wherein said doses of step b) are administered at least 3 times per day. 
     
     
       64. The method of  claim 31 , wherein said doses of step b) are administered at least 3 times per day. 
     
     
       65. The method of  claim 32 , wherein said doses of step b) are administered at least 3 times per day. 
     
     
       66. The method of  claim 33 , wherein said doses of step b) are administered at least 3 times per day.